Katherine A. McGlynn, Ph.D., M.P.H.
|Organization:||National Cancer InstituteDivision of Cancer Epidemiology & Genetics, Hormonal and Reproductive Epidemiology Branch|
|Address:||NCI Shady GroveRoom 7E104|
Dr. McGlynn received an M.P.H. in population studies from Tulane University and a Ph.D. in epidemiology from the University of Pennsylvania. She conducted postdoctoral research at Fox Chase Cancer Center in Philadelphia, PA, where she subsequently served as a faculty member prior to joining the Hormonal and Reproductive Epidemiology Branch in 1998. Dr. McGlynn was the recipient of an NIH Merit Award in 2006 her study of testicular cancer.
The incidence of both testicular cancer and primary liver cancer are increasing in many populations, although there is wide geographic and ethnic variability in their rates. The reasons for the increases in incidence of both tumors are not well understood. We are using a variety a study designs to investigate environmental and genetic risk factors that may contribute to the increasing rates.
Testicular germ cell tumors (TCGT) are the most commonly occurring malignancy among U.S. men between the ages of 15 and 40 years old. The incidence of the TGCT has been increasing for several decades, but the etiology remains poorly understood. The only well described risk factors are cryptorchidism, a personal history of testicular cancer and a family history of testicular cancer. To better understand the epidemiology of TCGT, we conducted, in collaboration with the Department of Defense, a large case-control study among members of the U.S. military. The aim of the Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) study was to examine a wide variety of endogenous and exogenous risk factors. Of particular interest to the investigation were exposures to endocrine disrupting chemicals, endogenous hormone levels, viral exposures, prenatal variables, and genetic susceptibility.
Although the hypothesis that endocrine disrupting chemicals may be related to the development of TCGT is not new, few examinations of the hypothesis have previously been reported. In the STEED study, pre-diagnostic sera were used to examine associations with organochlorine pesticides and polychlorinated biphenyl (PCB) compounds. The analysis found that men who developed TGCT had higher serum levels of p,p’-DDE, a metabolite of p,p’-DDT, and higher levels of two chlordane-related components, cis-nonachlor and trans-nonachlor, than did men who did not develop TGCT. In contrast, men who developed TGCT had significantly lower serum levels of PCBs. These combined results indicate that exposure to some endocrine disrupting pesticides may increase the risk of TGCT. Further examinations of the hypothesis are now underway.
An examination of perinatal factors in the STEED Study found that young maternal age (<20 vs. 20-29 years, OR = 1.51, 95%CI: 1.09-2.10), young paternal age (<25 vs. 25-29 years, OR = 1.45, 95%CI: 1.08-1.94), maternal parity (3 vs. 1, OR = 0.63, 95%CI: 0.44-0.90) and breech birth (OR = 1.92, 95%CI: 1.03-3.56) were associated with increased risk of TGCT. For seminomas, young maternal age (<20 vs. 20-29 years, OR = 1.67, 95%CI: 1.10-2.54), young paternal age (<25 vs. 25-29 years, OR = 1.53, 95%CI: 1.03-2.27), maternal parity (3 vs. 1, OR = 0.58, 95%CI: 0.35-0.96) and low birth weight (<2,500 g vs. 2,500-4,000 g, OR = 1.82, 95%CI: 1.00-3.30) were risk factors. Nonseminomas were associated with breech birth (OR = 2.44, 95%CI: 1.25-4.78) and Cesarean section (OR = 2.10, 95%CI: 1.25-3.54). These results support the hypothesis that TGCT may originate in very early life.
Body sizes, age at puberty and dairy food consumption have all been suggested to be related to the development of TGCT. To clarify the relation of these variables to TGCT risk and to one another, data from 767 cases and 928 controls in the STEED study were examined. Overall, increased height was significantly related to risk (odds ratio (OR) = 1.83, 95% confidence interval (CI): 1.36, 2.45), though body mass index was not (OR = 1.06, 95% CI: 0.66, 1.69). There was no association with age at puberty, based on ages at first shaving (OR = 1.29, 95% CI: 0.96, 1.73), voice changing (OR = 0.97, 95% CI: 0.71, 1.32), and nocturnal emissions (OR = 1.00, 95% CI: 0.73, 1.37). Similarly, there was no association with dairy food consumption at any age between birth and 12th grade. These results suggest that height is a risk factor for TGCTs, but the association is unlikely explained by childhood dairy food consumption. As adult height is largely determined in the first 2 years of life, increased attention to events in this interval may help elucidate the etiology of TGCTs.
Using a candidate locus approach, genetic susceptibility to TGCT has been examined in a number of analyses of STEED data. Genetic variation in several pathways have been studied: the hormone metabolism pathway, the inhibin pathway, insulin-like growth factor pathway, immune function pathway and genes related to height. Though the examination of each pathway found some suggestive associations, a strong association with a particular locus has not been definitively identified. Given that there are few well-established risk factors to guide candidate locus selection, the genetic susceptibility studies will now shift to a genome-wide association approach.
The effect of hormones on testicular cancer risk has been difficult to investigate because of the retrospective nature of most studies. In general, however, case-control studies reported that men with testicular cancer have higher follicle stimulating hormone levels and somewhat lower testosterone levels than controls. These observations suggest that testicular cancer arises in a state of "gonadotropin overdrive" in which the gonads have lost the ability to respond to gonadotropins. The STEED study is testing this hypothesis by examining gonadotropin levels in pre-diagnostic sera to determine whether higher levels are also seen prior to cancer diagnosis. Levels of steroid hormones are also being examined.
Primary liver cancer is the sixth most commonly occurring cancer in the world and the third largest contributor to cancer mortality. There is great variability in rates around the world, however. Approximately 80% of liver cancer occurs in east Asia and sub-Saharan Africa. In almost all geographic locations, hepatocellular carcinoma (HCC) is the dominant histologic type and intrahepatic bile duct cancer is the second most common type.
In most high-rate regions, chronic infection with hepatitis B virus (HBV) and consumption of foods contaminated with aflatoxin B1 (AFB1) are well-established risk factors for HCC. The majority of persons infected with HBV, however, do not develop HCC. As a result, we are continuing to look for other risk factors. Examining a population in central China, we found that serum levels of p,p’-DDT significantly increased risk of HCC. We are now confirming this association by examining a high-risk population in eastern China. In the same population, we are also studying whether fumonisin, a mycotoxin similar to aflatoxin, is related to increased risk of HCC.
In lower-rate HCC countries, such as the United States, excessive alcohol consumption, infection with hepatitis C virus (HCV) and infection with HBV are all related to increased risk. Pre-existing diabetes and obesity also appear to increase risk. The attributable risks of these factors, however, are not well defined. As a consequence, it is not clear what factors are driving the increase in incidence that has taken place in the United States since 1980. To examine this issue, we are currently analyzing data from the SEER-Medicare linkage. We are also heading a collaborative examination of HCC risk factors among U.S. Cohort Consortium studies. Finally, we are planning to conduct a large case-control study in collaboration with a health maintenance organization.
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Watch Dr. McGlynn discuss her research at the 2011 NIH Director’s Seminar Series.